Reovirus therapy stimulates endoplasmic reticular stress, NOXA induction, and augments bortezomib-mediated apoptosis

K R Kelly1, C M Espitia, D Mahalingam

  • 1Department of Medicine, The Institute for Drug Development, Cancer Therapy and Research Center, The University of Texas Health Science Center, San Antonio, TX 78229, USA.

Oncogene
|October 18, 2011
PubMed

Insights

Reolysin, a reovirus cancer therapy, induces apoptosis in multiple myeloma cells by triggering endoplasmic reticulum stress and NOXA protein. Combining Reolysin with bortezomib enhances anti-myeloma effects, reducing tumor burden with minimal side effects.

Area of Science:

  • Oncolytic virotherapy
  • Cancer biology
  • Molecular oncology

Background:

  • Reovirus demonstrates anti-cancer activity with low toxicity, but mechanisms remain unclear.
  • Reolysin, a reovirus formulation, selectively replicates in and induces apoptosis in multiple myeloma (MM) cells.

Purpose of the Study:

  • To elucidate the mechanisms of reovirus-mediated apoptosis in MM.
  • To investigate the synergistic effects of Reolysin and bortezomib in MM treatment.

Main Methods:

  • Assessed Reolysin's effect on MM cell apoptosis, ER stress markers, and NOXA protein.
  • Utilized short hairpin RNA to knock down NOXA expression.
  • Evaluated the combination of Reolysin and bortezomib in MM models.

Main Results:

  • Reolysin induced MM cell apoptosis via ER stress and NOXA upregulation.
  • NOXA knockdown diminished Reolysin's pro-apoptotic effects.
  • Combination therapy enhanced ER stress, NOXA induction, and apoptosis, significantly reducing tumor burden in vivo.
  • The combination therapy showed no adverse side effects.

Conclusions:

  • ER stress and NOXA induction are novel mediators of reovirus-induced apoptosis.
  • Reovirus infection potentiates bortezomib's anti-myeloma activity by increasing ER stress in MM cells.

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